JPS60202838A - Bicyclo(3.3.0)octene derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is 5-10C straight chain, branched or cyclic alkyl or alkenyl; R<2> and R<3> are H or protecting groups of OH; R<4> is OH, acetyloxy or butenyl). EXAMPLE:3-( 4'-Pentenyl )-6(S)-[3'(S)-tert-butyldimethylsilyloxy-1'-trans-octenyl]-7 (R)-tert-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene. USE:A raw material for 9(O)-methal-DELTA<6(9a)>-PGI1s, having powerful inhibitory action on blood platelet agglutionation, and useful as a remedy and preventing agent for various diseases in cardiovascular systems. PREPARATION:A compound expressed by formula II is reduced with a reducing agent to give the compound expressed by formula I (R<4> is OH), which is then acetylated to afford the compound expressed by formula I (R<4> is acetyloxy). The resultant compound is then reacted with a lithium dialkylcuprate to give the compound expressed by formula I (R<4> is butenyl).

Description

Detailed Description of the Invention The present invention is based on the general formula % (wherein R1 is a linear, branched or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms, B2 and R3 are hydrogen atoms or protecting hydroxyl groups) R4 is a hydroxyl group, and acetate V is a butenyl group.

The bicyclo[3°3.0]octene conductor represented by the general formula (I) of the present invention undergoes a deprotection reaction of the hydroxyl group after water reflection, and is further oxidized to produce 9(0)-methano-
Δ'(9″)-PGI 1 and its analogs (see reference side below).9(0)-methano-Δ6
(?0-PG11 has a strong clastic platelet aggregation inhibiting effect,
For example, when using human platelets, its action is comparable to that of the chemically unstable PGI2#, and it is a compound used as a treatment or preventive drug for various cardiovascular diseases (see test side below). .

Conventionally, the methods for producing 9(0)-methano-Δ6""-PGI 1 include (a) a method for producing 9(0)-methano-Δ6""-PGI 1 through 14 steps using PGD2 as a raw material [Pharmaceutical Society of Japan 103rd Annual Conference Proceedings, p. 156 (1983) )], (Method for producing l!IJ from 1,3-cyclooctadiene through 19 steps [Proceedings of the 103rd Annual Meeting of the Pharmaceutical Society of Japan, p. 157 (1983)]
and (c) a method of manufacturing from furfural through 12 steps (Proceedings of the 104th Annual Meeting of the Pharmaceutical Society of Japan (Sendai) p. 282)
However, in method (a), the raw materials are expensive, in method (b), the target product is produced as a racemate, and in both methods (o), the overall yield is very low. and (c)
The disadvantage of this method was that it was very difficult to purify the final product.

The present inventors have developed 9(0)-methano-Δ6(9″) from inexpensive raw materials in good yield and in an optically active form with stereospecific specificity.
As a result of repeated research in order to produce -PGll and its analogues, the present invention was completed by discovering that the compound of the present invention can serve as an important intermediate for achieving the objective.

The bicyclo[3°3.0]octene derivative represented by the general formula (1) of the present invention can be produced according to the following reaction formula.

In addition, the protecting group for the hydroxyl group in the present invention is a tetrahydropyranyl group, a methoxymethyl group, a 4-methoxytetrahydropyranyl group, a 1-ethoxyethyl group, a -methyl-1-methoxyethyl group, and a t-butyldimethylsilyl group as R2. , diphenyl-t-butylsilyl group, benzoyl group, acetyl group, triethylsilyl group, etc., and as R' and L, t-butyldimethylsilyl group, benzoyl group, acetyl group, tetrahydropyranyl group, methoxymethyl Examples include 4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, diphenyl-1-butylsilyl group, and triethylsilyl group.

The present invention can be prepared according to Reaction Scheme I below.

m26 oa' [First step] In this step, the bicyclo[3°3.0]octenylaldehyde derivative represented by the general formula (1) is reduced to form bicyclo(3 , 3°0] for producing octenyl methyl alcohol derivatives.

Among the bicyclo(3,3,03 octenyl aldehyde derivatives represented by the general formula (fil), which are the raw materials for this process, linear or branched compounds are used at the 104th Annual Meeting of the Pharmaceutical Society of Japan (Sendai) It can be produced by the method described in Proceedings, r1282, and compounds in which R1 is cyclic can also be produced by the same method (see reference side below).

This step needs to be carried out in the presence of a reducing agent. As the reducing agent, diisobutylaluminum hydride, sodium borohydride, lithium aluminum hydride, etc. can be used. The amount of the reducing agent to be used is based on the general formula (I
It is used in an amount equivalent to or slightly in excess of the bicyclo(3,3,0)octenylaldehyde derivative represented by I).

It is preferable to carry out this step in a solvent, such as alcohol solvents such as methanol and ethanol, ether solvents such as diethyl ether and tetrahydrofuran, aromatic solvents such as benzene and toluene, methylene chloride, and chloroform. For example, halogenated solvents such as halogenated solvents, etc. can be used, and they can be appropriately selected and used depending on the reducing agent used. The reaction proceeds at -100 to 50°C.

[Second process]

In this step, the bicyclo[3°3.0
] Bicyclo(3,
3,0) Octenyl methyl acetate derivatives are produced.

For acetylation, acetic anhydride, which is commonly used in this type of reaction, is used.

In carrying out this step, pyridine S4-dimethylaminopyridine or the like can be used as a catalyst.

This step is preferably carried out in a solvent, and aromatic solvents such as benzene and toluene, ether solvents such as diethyl ether and tetrahydrofuran, and halogen solvents such as methylene chloride can be used.

The reaction can be carried out at -25°C to 100°C.

(Third Step) In this step, the general formula (I-b) obtained in the second step is reacted, and copper iodide and 3-butenyl lithium represented by the general formula (1-C) are produced. is R, F, Cu
n1co, Y, -, Han, J+Organomet
.

Chem., 174, 247 (1979)) can be easily produced by reaction.

In carrying out this step, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc. can be preferably used.

The reaction can be carried out at -100°C to 50°C.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

1111 Example 1 (S1 winter wt-ike" Lerimekerv-, '7t 4)
(3-formyl-e(S)-(a'(s)-t-frucimethylsilyloxy-1'-trans-octenyl)-7(b)-t-butyldimethylsilyloxy-(
I.S.

58)-Cis-bicyclo(3,3,0)oct-2-cyclo(7) (4201rUJ, 0.83mmof) in toluene (3.5m) solution with diisobutylaluminum hydride (1,25mmol, 0.71m,
(1.75M hexane solution) was stirred at -78°C for 90 minutes. Methanol was added dropwise to the reaction solution until no hydrogen was generated, and then diluted with ether. Further, saturated brine was added and stirring was continued until the organic layer became transparent. After separating the ether layer, the ether extraction was repeated, and the ether layers were combined and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography.
-Hydroxymethyl-6(8)-(3°(s)-t-butyldimethylsilyloxy-1°-trans-offf=
/L/)-7(ro)-1-butyldimethylsilyloxy-(Is, 58)-cissuhikuo (3,3,0
) Oct-2-ene) (373yv, 88%) was obtained as an almost colorless oil.

IR (neat): 3350cm.

Subset δ (CDCl2) 5.47 (m, 3H), 4.13 (m, 3H), 3
．． 73 (m, 1) (), 2.97 (m, IH
) -Mass rr)/z:451(M+-57)
.

Example 2 (3-formyl-6(8)-(3'(S)-tetrahydropyranyloxy-1'-trans-octenyl)-7
(R)-tetrahydropyranyloxy-(Is, 58)
-cis-bicyclo(3,3,0)oct-2-ene) (
370yv, 0.83mmol) to (3-hydroxymethyl-6(S)-
[3'(S)-tetrahydrol-pyranyloxy-1'-
4 lance-octenyl)-7(R)-tetrahydrol-pyranyloxy-(Is, 58)-cis-bicyclo(:
3.3.0 ) oct-2-ene) (316 Akebono, 85
%) was obtained as an almost colorless oil.

IR (neat): 3345cm.

Mδ (CDCl2) 5.45 (m, 3H), 4.55 (m, 2H), 4.1
0 (m, 3H), 3.50~4.00 (m,
5H), 2.98 (m, IH).

Mass rr)/z: 364 (M+-84).

Example 3 (3-hydroxymethyl-6(S)(3'(s) -t
-butyldimethylsilyloxy-11-trans-octenyl)-7(R)-t-butyldimethylsilyloxy-(Is, 58)-cis-bicyclo(3,3,0)oct-2-4one) (97fPVI , 0.19 mmol
) of pyridine (1,5 m/ )? ! Add acetic anhydride (0,
29 mmo! , )27 μe) and a catalytic amount of 4-dimethylaminopyridine were added at room temperature, and the mixture was stirred for 30 minutes. A saturated aqueous copper sulfate solution was added to the reaction mixture, and the mixture was extracted with ether. The ether layer was washed with water and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain (3-acetoxymethyl-
6(8) -(3'(S) -t'-butyldimethylsilyloxy-11-trans-octenyl]-7(b)
-t-butyldimethylsilyloxy-(18,58)-
cis-bicyclo(3,3,0)oct-2-ene)(1
04m7, 100%)P Obtained as a colorless oil.

IR (neat): 1755cIL.

Shinhan, t (CDCl2) 5.47 (m, 3H), 4.55 (s, 2H), 4.0
1 (m, IH) e 3-68 (m -IH),
2-93 (''-IH) -2,05(S, 3H
).

Mass r, /z: 493 (M”-57).

Example 4 (3-Hydroxymethyl-6(S)-(3'(S)-tetrahydropyranyloxy-11-)lanse-octenyl)-7(R)-tetrahydrobiranyloxy-(18
,58)-cis-bicyclo(3,3,0)oct-2-
Example 3 from ($5q, Q, 19 mmol)
By exactly the same reaction procedure, (3-acetoxymethyl-6(S)-(3'(S)-tetrahydropyranyloxy-11-trans-octenyl)-7(R1-tetrahydropyranyloxy-(Is, 58 )-cis-bicyclo, (3,3,0)oct-2-ene) (93 Takumi, 10
0iR (nea) was obtained as an almost colorless oily substance.
t): 1750ffi.

NMRδ (CDCl2) 5.45 (m, 3H), 4.55 (m, 4H)
, 4.05 (m, IH) , 3.40-4.00
(m, 5H), 2.91 (m, IH), z, o5
(s, 3H).

Mass rrVZ: 406 (M+-84).

Example 5 Cupric iodide (1634,0,85 mmol)
Freshly prepared 3-butenyl rim f') membrane (1,70 mmol, 1.31 m1/, 1.
A 30M hexane solution) was added at -30°C, and the mixture was stirred for 30 minutes. After cooling the reaction solution to -78°C, (3-acetoxymethyl+6(S)(a'(8)-t-butyldimethylsilyloxy-11-trans-octenyl)-7@
-t-butyldimethylsilyloxy-(Is, 58)-
cis-bicyclo(3,3,0)oct-2-ene) (
213 Akebono.

0.39mmol) (7) THP (1m)
The solution was added and stirred for 1 hour under the same conditions. After further stirring at room temperature for 0.5 hour, the reaction was stopped with a saturated ammonium chloride aqueous solution.

After extraction with ether, the ether was washed with saturated saline and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain (3-(
4°-pentenyl)-6(8)-(3'(S)-t-butyldimethylsilyloxy-1-trans-octenyl]-7(ro)-t-butyldimethylsilyloxy-(I
s, 58)-cis-bicyclo(3,3,0:)octo-
2-ene) (1544,73ti) was obtained as an almost colorless oil. This substance contains about 10% of (2-(a'-butenyl)-3-methylidene-6(S)-(3°(S)-t)
-butyldimethylsilyloxy-1°-trans-octenyl)-(t8.s8) -cis-bicyclo(3,3
, 0) octane) IR, (neat): 1645m.

NMRδ (CDCl2) 5.40~6-05 (IHv m) Q5.35 (
Side 2m) v5.20 (approx. IH#b s) p
4-90 (crime, m) '7 8^/lp mN Q a
n(1u mN QQn (approximately IH, m).

Mass rr)/z:489(M+-57)-(3-
Acetoxymethyl-6(Sl-(3'(S)-tetrahydropyranyloxy-1'-trans-octenyl)-
7(ro)-tetrahydropyranyloxy-(Is, 58
)-cis-bicyclo(3,3,0)oct-2-x 7
) (191q, 0.39 mmol) was subjected to the same reaction procedure as in Example 5 to obtain (3-(4'-pentenyl) -e (S) -[3'fs)-tetrahydropyranyloxy-1-trans-octenyl ]-7-tetrahydropyranyloxy-(Is, 58)-cis-bicyclo(3,3,0)oct-2-ene) (x33m
g.

70) was obtained as an almost colorless oily substance.
o% of (2-(3'-butenyl)-3-methylidene-6(S)-(3'(S)-tetrahydropyranyloxy-11-trans-octeninoly-(Is, 58)-
cis-bicyclo(3,3,0)octane).

IR(neat): 1645cIIL.

1 piece (C'DCI3) 5.40~6.05 (IH, m), 5.35 (
2H, m).

5.20 (approximately IH, bs), 4.90 (2H, m).

4.55 (2H, m), 4.00 (IH, m),
3.40-3.70 (5H, m), 2.90 (about IH, m).

Mass rryz:402(M+-84) -Reference example 1 shi8IO081e ;5ig 0B1a((3-(4'
-pentenyl) -6(8)(3'<8)-t-butyldimethylsilyloxy-11-trans-octenyl)-7(R)-t-butyldimethylsilyloxy-(I
S,5S)-cis-bicyclo('3.3.0)oct-2-ene) (17511p, 0.32mmol
) (purity about 90%) in THF (1,2y) solution (0.42mmol I, 0.83m
, 0.5 M TH11i' solution) was subjected to θ℃ nite processing,
Stirred with I trowel under the same conditions for 5 hours ◇ After further stirring at room temperature for 0.5 hour, 6N NaOH aqueous solution (0,21*υ
and 30ts hydrogen peroxide solution (0.18+d).
After stirring at 60° C. for 1 hour, the reaction solution was diluted with water and extracted with ether. The ether layer was washed with saturated aqueous sodium thiosulfate and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography to obtain (3-(51-hydroxypentyl)-6(8)-(3'(S)-t-butyldimethylsilyloxy-1'-trans- octenyl)-7(
R)-t-butyldimethylsilyloxy-(18,58
)-cis-bicyclo(3,3,0)oct-2-ene)
(145 tnp, 81%) was obtained as a nearly colorless oil.

IR (neat): 3350 (m).

Width: a (CDCI,) 5.47 (m, 2H), 5.24 (m, I
H), 4.05 (m, iH), 3.64 (m, 3H)
, 2.91 (m, IH).

Mass rrVz: 507 (M+-57).

Reference example 2 (3-(4'-pentenyl)-6(S)-(3'(S)
)-tetrahydropyranyloxy-11-trans-octenyl]-7(5)-tetrahydropyranyloxy-
(t8,58)-cis-bicyclo(3,3,0)oct-2-xn) (156esy, 0.32mmol)
((3-(5'-hydroxypentyl) -6
(S)-(3゜(S)-tetrahydropyranyloxy-
11-trans-octenyl]-7(ha)-tetrahydropyranyloxy-(18,58)-cis-bicyclo(
3,3,0)oct-2-ene) (121■, 75%
) was obtained as an almost colorless oil.

IR (neat): 3400m.

NMRJ (CDC15) 5.45 (m, 2H), 5.24 (m, IH), 4.
60 (m, 2H), 4.05 (m, IH), 3.40~
3.70 (m, 7H), 2.91 (m, IH).

Mass ny’z: 420 (M+-84).

Reference example 3 (3-, (5-hydroxypentyl) -6(8) -
(3'(S)-t-butyldimethylsilyloxy-11
-trans-octenyl]-7(b)-t-butyldimethylsilyloxy-(18,58)-cis-bicyclo[
3゜3.0〕oct-2-x n) (22sny,
0.039 mmol) and tetra-n-butylammonium fluoride solution (Q, 3 mm 0 I, 0.3*/
, tMTHF solution) was added and stirred at room temperature for 12 hours. The reaction solution was diluted with saturated brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate-acetone, 95:5) and purified with (3-(5-hydroxypentyl)-6(S)-).
(3'(S)-hydroxy-11-trans-octenyl)-7(1'Q-hydroxy-(18,5S)-cis-bicyclo[3°3.0]oct-2-ene) (13■
, 100 g) was obtained as an almost colorless viscous liquid.

IR (neat): 3350cm NPvfRJ (CI)C' I! , )5.52(
m, 2H), 5.28 (bs, IH), 4.07 (m,
IH), 3.65 (m, 3H), 2.97 (m, IH)
.

Mass Vz: 318 (M+-18) - Reference example 4 (3-(5'-hydroxypentyl)-6(8)-(3
'β)-tetrahydropyranyloxy-1-trans-
octenyl]-70-tetrahydropyranyloxy-(
18,5s)-cis-bicyclo(3,3,0)octo-
2-ene) (20 sy, 0.040 mmoJ) was dissolved in a mixed solvent (1 group 1) of acetic acid-water-TIP (3:1:1) and heated at 60°C for 3 hours. After evaporating the solvent, a small amount of saturated water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sulfuric acid. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain %(3-(5'-hydroxypentyl)
-6(S) -(3'(8)-hydroxy-11-trans-octenyl)-7(R)-hydroxy-(Is
, 58)-cis-bicyclo(3,3,0]]octo2
-Ene (13K, 100%) was obtained as an almost colorless viscous liquid. Various spectral data were completely consistent with those obtained in Reference Example 3.

Reference example 5 (3-(5-hydroxypentyl)-6(S)-(3
'(81-hydroxy-1-trans-octenyl]-
7(ro)-hydroxy-(18,58)-cis-bicyclo(3,3,0)oct-2-ene) (12 towns, 0.
036 mmol) was dissolved in acetone-H2O (1:4,
1. Pt obtained by reducing PtO2 by dissolving it in
as a catalyst, baking soda (3.2q, 0.038mmol)
The mixture was stirred at 60° C. for 24 hours in an oxygen stream. The catalyst was filtered, neutralized with a 10% HCI aqueous solution, and then the acetone was distilled off.

The mixture was again made weakly acidic using a 10% HCI aqueous solution ζ, and then thoroughly extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off to give (+-1-
9(0)-methano-Δ””)-PGI, (8Tnf, 6
1%) was obtained as an almost colorless oily substance.

IR (neat): 3350, 1700, 1450, 1
250cIIL.

Width δ (CDCI5) 5.60 (m, 2H), 5.31 (ba, IH), 4.
11 (m*IH), 3.80 (m, IH), 3.00 (
m, IH).

0.90 (t, J:=6Hz, 3H).

Mass (CI, NH3) rry/z:36B (M
”-+-NH,).

[α);'=+x6°(:c==0.25, MeO
H) Reference Example 6 (2(b)-allyl-34-(3'(S)-1-butyldimethylsilyloxy-31-cyclopentyl-11-
trans-propenyl)-4cEQ-t-butyldimethylsilyloxy-1-cyclopentanone) (354tr
#! j, 0.72 mmol) of methylene chloride (7 z)
Zinc-titanium chloride methylene bromide reagent (Zn TiCl4-CH2Br2/THF, 3.
74m1. (approximately 1.3 equivalents) was added. After stirring for 30 minutes under the same conditions, the raw materials disappeared, so the reaction solution was poured into a two-layer system of ether-saturated aqueous sodium bicarbonate solution to stop the reaction. The ether layer was then separated and extracted with additional ether. The combined ether layers were washed with saturated ammonium chloride water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain (2(6)-allyl-3
(R)-(3 letters)-1-butyldimethylsilyloxy-
3-cyclopentyl-1'-) lance-propenyl)-
4(R)-t-Butyldimethylsilyloxy-1-cyclopentylidene) (32fimy, 8 to 0) was obtained as a nearly colorless oil.

IR(neat): 3078, 2930, 2850
, 1648.

1460.1360, 1.247cm.

Hadake,,t(CDCI,) 5,'70(m,IH),5.40(m,2H),4=
70-5.05 (m, 4H), 4.02 (m, IH
), 3.76 (IH, m), 2.00-2.60
(m, 6H), 1.38 (m, 9H), 0.8
8 (a, 18H), 0.02 (S.

12I().

Mass ry)/z:433(M+-57), 419
, 391° Reference Example 7 (2(ro)-allyl-34-(-t'(s)=t-butyldimethylsilyloxy-3'-cyclopentyl-1
'-trans-propenyl]-4(5)-t-butyldimethylsilyloxy-1 dicyclopentylidene) (69
0 (3,
3゜1] π1 solution of Nona7 (9-BBN) (7,10
m, mol.

14.2#I/) was added at room temperature and stirred for 3 hours. Next, 6N-NaOH aqueous solution (6.9w), 30
A tlAH202 aqueous solution (5.8 mυ) was slowly added dropwise at room temperature and stirred at 60°C for 2 hours. The reaction solution was extracted with ether, and the ether layer was extracted with a sodium thiosulfate aqueous solution,
Washed with water. After drying with anhydrous magnesium sulfate I trowel,
The solvent was distilled off, the residue was purified by silica gel column chromatography, and rl(S)-hydroxymethyl-2(S)
-(3'-hi Yo Kishifu o Hill) -3(s) -(
3'(S)-t-butyldimethylsilyloxy-3'-
Cyclohentyl-1l-trans-propenyl]44@
-t-phthyldimethylsilyloxycyclopentane) (
442 m, z, 59 wings were obtained as a colorless oily substance.

IR (neat): 3345, 2920, 2850, 1
456°1360.1246cm.

Foil IRδ (CDCI,) 5.35 (m, 2H), 3.95 (m, 2H), 3.
59 (m, 4H), 2.16 (m, 4H)
, 1.10-1.80 (m, 16H) -0-8
7(sp 1 gH)FO-04(''-12H)
-Mass Vz: 469 (M+-57), 451.
394,377°-11111 Reference Example 8 Under exactly the same conditions as Reference Examples 6 and 7, (2(R)-allyl-3(R)-(3°(S)-tetrahydropyranyl) oxy-3'-cyclopentyl-11) lansuprohenyl) -4(FQ-tetrahydropyranyloxy-1-
(1(8)-Hydroxymethyl-2(8)-
(31-hydroxypropyl) -3(8) -(3'
(S)-tetrahydropyranyloxy-31-cyclopentyl-1'-trans-propenyl]-4(b)-tetrahydropyranyloxycyclopentane) (275q
) was obtained as an almost colorless oil.

IR (neat): 3350, 2930, 2850, 1
450°1365.1200°.

Ground assembly δ (CDCI5): 5.34 (m, 2H), 4.50 (m, 2H), 4.0
0 (m, 2H), 3.60 (m, 8H).

Mass rrlz: 466 (M+), 448° Reference Example 9 MiSiO”・70S1ri1!: Si0 08iζ Oxalyl chloride (0.46m/, 5.40mmol
) to methylene chloride solution (5d) of R80 (0.83m,
11.7 mmol) c7) Methylene chloride solution (4 mg)
was added over 5 minutes at -78°C, and stirred under the same conditions for 15 minutes. To this (1(S)-hydroxymethyl-2(S)
)-(3“-hydroxypropyl)-3(S)-(3
'(S)-t-butyldimethylsilyloxy-3-cyclopentyl-11-trans-propenyl)-4(R1
-t-butyldimethylsilyloxycyclopentane) (
473ml.

0.900 mmol) of methylene chloride (3d) solution was added dropwise, and the mixture was further stirred at -78°C for 15 minutes. Under the same conditions, triethylamine (2.50 mg, 18.0 mm
ol) was added, the cooling bath was removed, and the mixture was stirred for 15 minutes. Methylene chloride was distilled off under reduced pressure, and benzene (
8#I/) and trifluoroacetate of dibenzylamine (220ml, 0.900mmol) were added and stirred at 70°C for 4 hours. The reaction solution was diluted with ether, and diluted with aqueous ammonium chloride solution and saturated sodium hydrogen carbonate. It was washed with an aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography.
8) -t-Butyldimethylsilyloxy-31-cyclopentyl-11-trans-propenyl]-7(b)-
t,-butyldimethylsilyloxy-(Is, 58)-
cis-bicyclo(3,3,0)oct-2-ene) (
385machi, 8yaku0 was obtained as an almost colorless oil.

IR(neat):'2950, 2850, 1675,
1450°136 (D, 1250cm.

ma (CDCI,) 9.82 (' p IH) -6-72 (b s -
IH) P 5-45 (m, 2H), 4.05 (
m, IH), 3.7 e (m, IH).

3.23 (m, IH), 1.10-2.80 (m, 1
5H).

0.87, 0.90 (28, 18H), 0.03 (8° 12H).

Mass rrS/z: 447 (M+-57), 43
3, 357.337°315.301,200,71
゜Reference Example 10 0THPOTHP In the same manner as Reference Example 9, (1(8)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(8
)-(3'(S)-tetrahydropyranyloxy-3-
cyclohentyl-1'-trans-propenyl]-4(
6)-tetrahydropyranyloxycyclopentane) (
2751V, 0.74 mmol) with a yield of 68% (
3-Formyl-6(S)-(3'(8)-tetrahydropyranyloxy-'31-cyclopentyl-1'-trans-propenyl)-7cfQ-tetrahydropyranyloxy-(18,58)-cis-bicyclo (3,3,0
) oct-2-ene) (223fflp) was obtained as an almost colorless oil.

IR (neat): 2950, 2850, 1680cI
l.

CDCl,) 9-81 (' p IH) -6-74 (b se
IH) -5-45 (m, aim), 4.48 (m, crime)
, 3.20-4.10 (m, 7H).

Mass n7z: 444 (M+), 359° Example 7 -3-cyclopentyl-1'-)lans-flobenyl]-7(to)-1-butyldimethylsilyloxy-
(18,58)-cis-bicyclo(3,3,0)oct-2-ene) (4184,0,83 mmol) to (
3-hydroxymethyl-6(8)-(3'(8)-1-
butyldimethylsilyloxy- -trans-propenyl]-7@-t-butyldimethylsilyloxy-(1B,58)-cis-bicyclo(3,
3,0)oct-2-ene) (37, 86) was obtained as a nearly colorless oil (near: 3350 cm).

NMRJ (CI) CI5) s, 4s (m, 3H), 4. x3 (m, 3H), a, 7
゜(m, II(), 2.98 (m, IH)
-Mass rryz: 449 (M+-57).

Example 8 The reaction procedure was exactly the same as in Example 1. propenyl)-7(R)-tetrahydropyranyloxy(Is
, 5B)-cis-bicyclo(3,3,0)oct-2-
en) (368q, 0.83mmo+) to (3-1F
Roxymethyl-6(8)-(3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-11-trans-propenyl]-74-tetrahydropyranyloxy-(Is, 58)-cis-bicyclo[3 ,3,0)oct-2-ene) (ao6q, s3%) was obtained as an almost colorless oil.

IR (neat): 3345cm.

NMRJ (CDC13) 5.45 (m, 3H), 4.55 (m, 2
H), 4.10 (m, 3H), 3.50-4.00
(m, 5H).

2.9 s (m, tH).

Mass rrVz: 362 (M+-84).

-M-1111 Example 9 By the same reaction procedure as in Example 3, (3-hydroxymethyl-6(8)-(3'(S)-t-butyldimethylsilyloxy-3-cyclopentyl- 1'-trans-flobenyl)-7(R)-t-phthylsimethylsilyloxy(18,58)-cis-bicyclo(3,3,0
) oct-2-ene) (96WI, 0.19mno
l ) from [3°-acetoxymethyl-6(8)-(3
'(8)-t-Butyldimethylsilyloxy-31-sifucyclot-butyldimethylsilyloxy-(IS, 5
8)-cis-bicyclo(3,3,0)oct-2-ene) (103 Cape.

100 g) was obtained as a colorless oil.

IR (neat): 1755cm.

NMR, t (CDC13) 5.47 (m, 3H), 4.54 (6,2H), 4.0
0(”e IH) v 3-68 (rn-tH)
, 2.92 (rn, IH).

2.05 (s, 3H).

Mass n7z: 492 (M+-57).

Example 10 Using exactly the same reaction procedure as Example 3, (3-hydroxymethyl-6(S)-[3''(S)-tetrahydropyranyloxy-3-cyclopentyl-1'-trans-propenyl)-7CfQ -Tetrahydropyranyloxy-
(18,58)-cis-bicyclo(3,3,0)oct-2-ene) (84tQ, 0.19mmol
) to (3-acetoxymethyl-6(S)-(3'(
S)-tetrahydropyranyloxy-3'-cyclopentyl-11-trans-propenyl)-7(R)-tetrahydropyranyloxy-(Is, 58)-cis-bicyclo[: 3.3°0]octo-2 -en) (91■,
100 g) was obtained as an almost colorless oil.

IR (neat): 1750cIIL.

Subset δ (CDCl2) 5.45 (m, 3H), 4.55 (m, 4H), 4.0
5 (m, IH), 3.40-4.00 (m,
5H), 2.91 (m, IH), 2.05
(s, aH).

Example 11 By the same reaction procedure as in Example 5, %(3-acetoxymethyl-6(S)-(3'(S)-t-butyldimethylsilyloxy-31-cyclopentyl-11-trans- propenyl)7(R)-1-butyldimethylsilyloxy-(18,5s)-cis-bicyclo(3,3
,0)oct-2-ene) (211■, 0.391
1・mmo 1 ) 7> et al (3-(4'-pentenyl)
-6(S) (3'(S) t-butyldimethylsilyloxy-3'-cyclopentyl-11-trans-propenyl)-7(R)-1-butyldimethylsilyloxy-(Is, 58)-cis- Bicyclo(3,3,0
) Oct-2-ene) (i49my, 70%) P was obtained as a colorless oil.

This substance also contained about 10% of a substance generated by γ-attack.

IR, (neat): 1645cm.

δ(CDCl2) 5.40+6.05 (IH, m), 5.35 (
2H, m).

5.20 (about IH, bs), 4.90 (2H, m).

4.00 (xH, m), 3.60 (tH, m)
, 2.90 (approximately IH, m).

Mass rryz: 487 (M+-57).

Example 12 By the same reaction procedure as in Example 5, (3-acetoxymethyl-6(8)-(3'(S)-tetrahydropyranyloxy-31-cyclopentyl-1'-trans-
(190w), 0.39mmo
1) to (3-(4-pentenyl)-6(S)-(
3'(S)-tetrahydropyranyloxy-31-cyclopentyl-1'-trans-propenyl]-7(b)
-Tetrahydrobitenyloxy(Is, 58)-cis-bicyclo[3°3.0]oct-2-ene) (131
70) was obtained as an almost colorless oily substance. This material also contained about 10 g of material produced by γ-bombardment.

IR (neat): 16451m.

NMFLa (CDCl3) 5.40-6.05 (IH, m), 5.35 (
2H, m).

5.20 (approximately IHe b s ) t 4-90 (
2) i#m) v4.55 (2H, m), 4.00 (I
H, m), 3.40-3.70 (5H, m), 2
．． 90 (about IH, m).

Mass rriz: 400 (M+-84).

By the same reaction operation as in Reference Example 1, (3-(4'-
hairtenyl) -6(S)-(3'(S) -t-furdimethylsilyloxy-31-cyclopentyl-1
1-trans-propenyl)-7(R)-t-butyldimethylsilyloxy-(is, 58)-cis-bicyclo(3,3,03oct-2-ene) (173■, 0
．． 32 mmo I) (purity approximately 190 cm) Kara (3-
(5'-hydroxypentyl) -6(S)-(3'(
S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-)lans-propenyl)-7(R)-
t-Butyldimethylsilyloxy-(18,5s)-cis-bicyclo(3,3,0)oct-2-ene) (1
40cm and 80cm λ were obtained as colorless oily substances.

IR (neat): 3350cm.

Konkua (CDCl2) 5.47 (m, 2H), 5.24 (m, IH), 4.0
5 (m-IH), 3.64 (rrr e 3H)
-2-91 (m, IH).

Ma; ss, rriz: 505 (M+-57).

Reference Example 12 By the same reaction procedure as in Reference Example 2, (3-(4'-
pentenyl) -6(8)-(3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1-trans-propenyl)-7(R)-tetrahydropyranyloxy-(18,58)-cis- Bicyclo (3,3゜0)
Oct-2-ene) (154mp, 0.32mmo
(3-(5'-hydroxypentyl')-6(8)-(3'(81-tetrahydropyranyloxy-31-cyclopentyl-1-trans-propenyl)-7(R) -tetrahydropyranyloxy-(18,58)-cis-bicyclo(3,3,0)
Oct-2-ene) (115%, 72%) was obtained as an almost colorless oil.

IR (neat): 3400cm.

NMRa (CDCI 3) 5.45 (m, 2H), 5.24 (m, IH), 4.6
0 (m, 2H), 4.05 (m, IH),
3.40-3.70 (m, 7H), 2.9t (m, x
H)-Maas n7z: 418 (M+-84)
.

Reference Example 13 Vessel ♂H By the same reaction procedure as in Reference Example 3, (3-(51-
Hydroxypentyl)-6(S)-C3 Dormitory)-1-butyldimethylsilyloxy-31-cyclopentyl-1
'-trans-propenyl)-7(R)-t-butyldimethylsilyloxy-(IS, 58)-cis-bicyclo(3,3,0)oct-2-ene) (21410,0
39mmol)75) et al. (3-(5'-1=Ft:
lxyhentyl) -6(S) -(3'(S)-hydroxy-3'-cyclopentyl-11-trans-propenyl)-7(ro)-hydroxy-(18,58)-cis-bicyclo(3,3 ,0]oct-2-ene)(12
tnI, 10←0 was obtained as an almost colorless viscous liquid.

Engineering R ("ea t): 3350cm-'.

NMRδ (CDCl2) 5.52 (m, 2H), 5.28 (bs, IH), 4.
07 (m, IH), 3.65 (m, 3H), 2.97 (
m, IH).

Mass rrB/z: 316 (M+-18).

Reference Example 14 By the same reaction procedure as in Reference Example 4, (3-(5゛-
hydroxypentyl') -6(8)-(3'(8)~
Tetrahydropyranyloxy-3-cyclopentyl-1
'-)5supropenyl]-7(b)-tetrahydropyranyloxy-(18,58)-cis-bicyclo(3
,3,0)oct-2-ene)(19■,0.040m
mo 1 ) from (3-(5-hydroxypentyl)-
6(S)-C3'(B)-hydroxy-31-cyclopentyl-1-trans-propenyl]-7(ro)-hydroxy-(18,5S)-cis-bicyclo(3,3,0
) oct-2-ene) (12 ml, 100*) t- was obtained as a colorless viscous liquid. The various spectral data completely matched those obtained in Reference Example 13. Reference side 15 By the reaction operation exactly the same as in Reference Example 5, (3-(s+-
hydroxypentyl)-6(S)-(3'(S)-hydroxy-3-cyclopentyl-11-trans-propenyl)-7(6)-hydroxy-(18,55)-cis-bicyclo(3,3, 0) oct-2-ene) (11
1"l e 0.036 mmol (3-C4'-carboxybutyl)-6(8)-(3'(8)-hydroxy-3-cyclopentyl-11-trans-propenyl)-7(ro)-hydroxy -(18,58)-cis-
Bicyclo(3,3°0]oct-2-ene) (7glI
, 60chi) was obtained as a colorless white solid.

Melting point: 115-116°C (recrystallized from ethyl acetate-n-hexane) IR (KBr): 3430, 2960, 1700.16
55cm.

NMRJ (CDCl 5) 5.62 (2H, m), 5.32 (IH, bs), 3.
90 (2H, m), 3.00 (IH, m).

Mass (CI, NH3) rry'z: 366 (M + 10 NH4) - Test Example 1 (G) -9 (0) - Methanol - Δri "' - PGI 1
has the following biological activities. When rabbit blood was used, platelet aggregation induced by adenosine diphosphate (ADP) was suppressed by the strength of PGI2 R, and l
.

Furthermore, when human blood was used, it showed strength comparable to that of PGI2. Regarding the effect on blood pressure, 4P was used in rats.
It showed the same strength as G■2, and showed a blood pressure lowering effect at a dose of 0.1 μg At. The impact on the knowledge level is also PG.
The strength is almost the same as that of I2, and in experiments using rats, a dose of 1 µm showed an increase in the degree of anxiety. It also showed anti-ulcer activity at a concentration as low as 10 M in experiments using rabbit stomachs, which is comparable in strength to PGE2. Cytotoxicity is very weak, IC5o = 5μgAt
It is.

Test Example 2 (a)-3-(4'-carboxybutyl)-6(S)
-(3'(S)-hydroxy-3'-cyclopentyl-
1'-trans-propenyl)-7(R)-hydroxy-(IS.

58)-cis-bicyclo(3,3,0)oct-2-ene has the biological activities described below. rabbit helmet (ra)
bbit stomach epithelial c
The method of Nitride et al.
a, Y Mj tsui, and S, Muiota, J
, Pharm, Dl! ! , ,i, 911 (1982
)) When the following experiments were carried out, it showed a significant anti-ulcer effect at a concentration as low as 0.5×10 M. This is because the carbacyclin analogs mentioned above have a diarrhea-inducing effect compared to O20, which has an activity strength comparable to that of Pα, a typical prostaglandin with an anti-ulcer effect, which induces severe diarrhea. do not have.

Patent Applicant Procedures Amendment (Spontaneous) June 18, 1985 Commissioner of the Patent Office Gakudono Shiga1, Indication of the Case Showa 59 Steel Patent Application No. 58458 No. 2 Name of the invention Bicyclo(3,3,0)octene Derivative 3, person making the amendment 5, content of amendment 1) Correct "3" to "3'" in line 7 on page 34 of the specification of the present application.

0'I) IF 0TI (P J 3) Correct "Shifushikuro" to "Cyclo" on page 41, line 11.

that's all

Claims (1)

[Scope of Claims] A bicyclo(3,3,0)octene derivative (
In the formula, R1 is a linear, branched or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms, W and R3 are a hydrogen atom or a protecting group for a hydroxyl group, R4 is a hydroxyl group, and acetym is a It is a butenyl group. ).